Project Summary An emerging body of literature has demonstrated the importance of non-coding DNA regulatory sequences in epigenetic and transcriptome regulation. Mutations of distal enhancers or enhancer binding proteins are identified as onco-drivers in a variety of cancers. They lead to deregulation of tumor suppressors and oncogenes, which in turn influence cancer initiation and progression. In our study, we propose to examine the function of transcription factor HOXA9 in enhancer regulation and how it may contribute to leukemogenesis. We will examine global changes in epigenome, with a focus on distal regulatory enhancers, in multiple acute myeloid and lymphoblastic leukemia models that have HOXA9 overexpression. We will identify recurrent HOXA9-dependent epigenetic alterations at distal enhancers and evaluate their potential as the therapeutic targets. We will also examine the mechanisms by which HOXA9 establishes open chromatin state at distal enhancers. Given extremely poor prognosis of acute leukemia with HOXA9 overexpression as well as the lack of good therapeutic options, in-depth mechanistic understanding of HOXA9 function in leukemogenesis will provide better options against the daunting clinical challenges. This project fits the mission of National Cancer Institute (NCI).